It has been reported that the multidrug-resistance/P-glycoprotein (mdr/pgp) gene is overexpressed in many mouse hepatocellular carcinoma (HCC) models, irrespective of carcinogenic regimens. This finding suggests that mdr gene expression may be a useful phenotypic marker to test the hypothesis that different hepatocarcinogenetic pathways in different HCC models may be converged in tumor development. To test this hypothesis, we propose here using in situ hybridization and immunocytochemical analyses to investigate mdr gene expression at the single cell level in various HCC models, including transgenic mice carrying liver targeted expression of hepatitis B viral large envelope protein gene and SV40 T-antigen gene which develope HCC following synchronous and predictable pathogenetic kinetics. This study may help us to understand the evolution of drug-resistance during hepatocarcinogenesis. Furthermore, these mouse HCC models may offer an attractive system for investigation on molecular mechanism of mdr gene activation during oncogenesis. Approaches to delineate the molecular mechanisms of mdr gene expression at transcriptional and/or posttranscriptional levels in established HCC-derived cell lines and primary HCC cells are proposed. These studies may provide important insights into the molecular basis of gene expression during hepatocarcinogenesis. In addition, we propose to determine the levels of mdr mRNA in human HCC in hoping to gain a preclinical assessment on the possible role of mdr gene expression in the intrinsic drug-resistance of this disease. This study is clinically relevant and may lead to development of effective chemotherapeutic strategy in combating human HCC.